Containter for mixing and dispensing two components

ABSTRACT

A container and methods for storing and mixing a two-component composition is provided. The container includes a body, a first plug and a second plug. The body has a first end, a second end, and a bypass with a length L disposed between the first and second ends. The first and second plugs are slidably disposed in the body and define a first compartment. A second compartment is disposed in the body between the second plug and the second end. The second plug has a first edge, a second edge, and a plurality of spaced-apart primary conduits extending through the second plug. Each primary conduit has a separate first opening. A distance D extends longitudinally from the first edge to the second edge and a distance E extends longitudinally from the first edge to the first opening that is nearest the first edge. D≧L and E&lt;L.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationNo. 62/098,070, filed Dec. 30, 2014, the disclosure of which isincorporated by reference in its entirety herein.

BACKGROUND

A standard hypodermic syringe comprises a cylindrically tubular bodyhaving a front end closed by a plug formed with a central passageextending along the axis of the body and a rear end provided with apiston longitudinally axially displaceable in the body. A quantity ofliquid to be injected is held in the body between the piston and theplug and a needle is fitted to the passage at its front end so thatforward displacement of the piston by a plunger forces the liquid out ofthe body through the needle.

A syringe for one-time use is frequently supplied already containing alyophilized medicament, to which some solvent, for instance sterilewater, is added to make the dried medicament injectable. To prepare thesyringe for use a needle is mounted on the front end of the body and theliquid is drawn into it.

It is also possible as described in U.S. Pat. No. 4,874,381 for there tobe two pistons, namely a front piston that subdivides the interior ofthe body into a rear compartment holding the dry medicament and a frontcompartment holding a solvent, typically water, for it. In this case thebody is formed with a bypass that permits mixing of the medicament andthe liquid on axial displacement of the pistons. A rear piston isadvanced to eject the contents.

In both systems the syringe is initially prepared by filling into thebody a quantity of the dissolved medicament and then lyophilizing it anddriving off the vaporized solvent, which escapes through the open frontend of the cylinder. While maintaining sterility the front end isplugged, and the thus prepared syringe is then fitted with the necessarytip cap or the like, and is bagged.

Such an arrangement is not readily susceptible to mass production, as itis necessary to hold down costs of this throwaway item. In factproduction is fairly difficult in view of the problems associated withplugging the cylinder end while maintaining the syringe and its environssterile.

SUMMARY

The present disclosure generally relates to a container for isolating(for storage) two components and, subsequently, rapidly and easilybringing the two components together in the container. Optionally, thecontainer can also be used to distribute the mixture of the components.Although particularly useful for storing and reconstituting dehydratedpharmaceutical preparations, a person having ordinary skill in the artwill recognize the container and method is useful for storing andpreparing a variety of reconstitutable compositions. The turbulencegenerated by a second plug disposed in the inventive containerfacilitates rapid dissolution and/or dispersion of a solid component ina liquid reconstitution medium.

In one aspect, the present disclosure provides a container. Thecontainer can comprise a body, a first plug and a second plug. The bodyhas a longitudinal axis, a first end with a first aperture, a second endincluding a second aperture opposite the first end, and a bypass havinga length L disposed between the first and second ends. The first plugcan be slidably disposed in the body proximate the first end. The secondplug can be slidably disposed in the body between the first plug and thesecond end. The first and second plugs can define opposite ends of afirst compartment disposed in the body between them. A secondcompartment can be disposed in the body between the second plug and thesecond end. The second plug can include a top surface facing the firstplug; a bottom surface facing the second end; a side wall extendingbetween the top surface and the bottom surface, the side wall comprisinga circumferential first seal having a first edge proximate the topsurface and a circumferential second seal having a second edge proximatethe bottom surface; and a plurality of spaced-apart primary conduitsextending through the second plug, each primary conduit extending fromseparate first openings in the side wall to a second opening in thebottom surface. The first opening is disposed between thecircumferential first seal and the circumferential second seal. At leastone of the primary conduits can direct liquid flow out of the secondopening along a line that is not parallel to the longitudinal axis. Adistance D extends longitudinally from the first edge to the second edgeof the second plug, a distance E extends longitudinally from the firstedge to the first opening that is nearest the first edge and D≧L andE<L.

In another aspect, the present disclosure provides a method of mixingfirst and second components of a composition. The method can compriseproviding a container according to any one of the above embodiments,wherein the container has the first component disposed in the firstcompartment and the second component disposed in the second compartment.The method further can comprise bringing the first component intocontact with the second component. The first component can comprise afluid. The second component can comprise a fluid or a solid. Bringingthe first component into contact with the second component can compriseurging the first plug toward the second end until at least one firstopening is in fluid communication with the bypass, the firstcompartment, and the second compartment. Urging the first plug towardthe second end can comprise urging at least a portion of the firstcomponent from the first compartment into the second compartment.

In yet another aspect, the present disclosure provides a method ofmixing first and second components of a composition and distributing thecomposition. The method can comprise providing a container according toany one of the above embodiments, wherein the container has the firstcomponent disposed in the first compartment and the second componentdisposed in the second compartment. The method further can comprisebringing the first component into contact with the second component. Thefirst component can comprise a fluid. The second component can comprisea fluid or a solid. Bringing the first component into contact with thesecond component can comprise urging the first plug toward the secondend until at least one first opening is in fluid communication with thebypass, the first compartment, and the second compartment. Urging thefirst plug toward the second end can comprise transferring apredetermined volume of the first component from the first compartmentinto the second compartment to form the composition. After thepredetermined volume of the first component is transferred into thesecond compartment, urging the first plug toward the second end furthercomprises urging the second plug toward the second end. Urging thesecond plug toward the second end comprises distributing at least aportion of the composition out of the body via the second aperture. Inany of the above embodiments, converting the second end of the containerfrom a closed state to an open state comprises converting a fluid-tightseal from a closed state to an open state. In any of the aboveembodiments, the method further can comprise coupling the second end toan infusion device.

The terms “comprises” and variations thereof do not have a limitingmeaning where these terms appear in the description and claims.

As used herein, “a,” “an,” “the,” “at least one,” and “one or more” areused interchangeably. Thus, for example, a channel can be interpreted tomean “one or more” channels.

The term “and/or” means one or all of the listed elements or acombination of any two or more of the listed elements.

Also herein, the recitations of numerical ranges by endpoints includeall numbers subsumed within that range (e.g., 1 to 5 includes 1, 1.5, 2,2.75, 3, 3.80, 4, 5, etc.).

The above summary of the present invention is not intended to describeeach disclosed embodiment or every implementation of the presentinvention. The description that follows more particularly exemplifiesillustrative embodiments. In several places throughout the application,guidance is provided through lists of examples, which examples can beused in various combinations. In each instance, the recited list servesonly as a representative group and should not be interpreted as anexclusive list.

Additional details of these and other embodiments are set forth in theaccompanying drawings and the description below. Other features, objectsand advantages will become apparent from the description and drawings,and from the claims.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a schematic side view of one embodiment of a body of acontainer according to the present disclosure.

FIG. 2 is a top view of the body of the container of FIG. 1.

FIG. 3 is a schematic side view, partially in section, of one embodimentof a container according to the present disclosure.

FIG. 4A is a bottom view of the second plug of FIG. 3.

FIGS. 4B and 4C are side view of the second plug of FIG. 3.

FIG. 5 is a side view of the second plug of FIG. 3, showing certaindimensional features and showing the relationship of the primaryconduits to the longitudinal axis of the second plug.

FIG. 6 is a side view of the body and the second plug of FIG. 3 showingcertain dimensional relationships of the features of the bypass and thesecond plug.

FIG. 7 is a schematic side view, partially in section, of one embodimentof a container according to the present disclosure, wherein thecontainer holds a first component in the first compartment and a secondcomponent in the second compartment, and wherein the second plug isdisposed in a first operational position with respect to the bypass.

FIG. 8 is a schematic side view, partially in section, of the containerof FIG. 7, wherein the second plug is disposed in a second operationalposition with respect to the bypass.

FIG. 9 is a schematic side view, partially in section, of the containerof FIG. 8, wherein the entirety of the first and second components areblended in the second compartment and the first and second plugs arepositioned to expel the blended components out of the container.

FIG. 10 is a schematic side view of the container of FIG. 9 showing theexpulsion of its contents after removal of the seal.

FIG. 11 is a schematic side view of one embodiment of a second plughaving a shaped bottom surface according to the present disclosure.

FIG. 12 is a schematic side view of an alternative embodiment of asecond plug having a shaped bottom surface according to the presentdisclosure.

FIG. 13 is a schematic side view of an alternative embodiment of asecond plug having a shaped bottom surface according to the presentdisclosure.

DETAILED DESCRIPTION

Before any embodiments of the present disclosure are explained indetail, it is to be understood that the invention is not limited in itsapplication to the details of construction and the arrangement ofcomponents set forth in the following description or illustrated in thefollowing drawings. The invention is capable of other embodiments and ofbeing practiced or of being carried out in various ways. Also, it is tobe understood that the phraseology and terminology used herein is forthe purpose of description and should not be regarded as limiting. Theuse of “including,” “comprising,” or “having” and variations thereofherein is meant to encompass the items listed thereafter and equivalentsthereof as well as additional items. Unless specified or limitedotherwise, the terms “connected” and “coupled” and variations thereofare used broadly and encompass both direct and indirect connections andcouplings. Further, “connected” and “coupled” are not restricted tophysical or mechanical connections or couplings. It is to be understoodthat other embodiments may be utilized and structural or logical changesmay be made without departing from the scope of the present disclosure.Furthermore, terms such as “front,” “rear,” “top,” “bottom,” and thelike are only used to describe elements as they relate to one another,but are in no way meant to recite specific orientations of the device,to indicate or imply necessary or required orientations of the device,or to specify how the invention described herein will be used, mounted,displayed, or positioned in use.

The present disclosure generally relates to a container for initiallyholding in separate compartments two components to be mixed, forsubsequently bringing together the two components and for distributingthe resulting combination of the two components. In addition, thepresent disclosure relates to methods of preparing the container withthe isolated components therein and to methods of using the container tocombine and, optionally, distribute the resulting combined components.Advantageously, the container of the present disclosure providesimproved mixing of the components during use.

The present disclosure provides a container. In any embodiment, thecontainer comprises:

-   -   a body having a longitudinal axis, a first end with a first        aperture, a second end including a second aperture opposite the        first end, and a bypass disposed between the first and second        ends;        -   wherein the bypass has a length L;    -   a first plug slidably disposed in the body proximate the first        end;    -   a second plug slidably disposed in the body between the first        plug and the second end;        -   wherein the first and second plugs define opposite ends of a            first compartment disposed in the body between them;        -   wherein a second compartment is disposed in the body between            the second plug and the second end;        -   wherein the second plug includes:            -   a top surface facing the first plug;            -   a bottom surface facing the second end;            -   a side wall extending between the top surface and the                bottom surface, the side wall comprising a                circumferential first seal having a first edge proximate                the top surface and a circumferential second seal having                a second edge proximate the bottom surface; and            -   a plurality of spaced-apart primary conduits extending                through the second plug, each primary conduit extending                from separate first openings in the side wall to a                second opening in the bottom surface;            -   wherein the first opening is disposed between the                circumferential first seal and the circumferential                second seal            -   wherein at least one of the primary conduits directs                liquid flow out of the second opening along a line that                is not parallel to the longitudinal axis;            -   wherein a distance D extends longitudinally from the                first edge to the second edge;            -   wherein a distance E extends longitudinally from the                first edge to the first opening that is nearest the                first edge;        -   wherein D≧L and E<L.

A container according to the present disclosure has a body (e.g., atubular body) having an interior volume and extending along and centeredon an axis. The body has at an axial first end with a first aperturethat provides access to at least a portion of the inner volume of thebody. The body has at an axial second end a second opening opposite thefirst aperture.

In any embodiment, the second end further comprises a couplingstructure. The coupling structure may be adapted to couple the containerto a needle or a microneedle device, for example. Non-limiting examplesof suitable coupling structures include Luer fittings (e.g., Luer-slipand Luer-lock type fittings) that are well known in the art. In anyembodiment, the coupling structure can couple the container to aninfusion device. Nonlimiting examples of infusion devices include acatheter, a cannula, a needle, or a microneedle device.

There are pharmaceutical compositions which, in a liquid state, veryrapidly lose their efficacy. To enable these compositions to be used inspite of their short shelf life, special devices and methods oflyophilization have been developed. Thus, pharmaceutical preparationswhich cannot be used in solution over long periods may be made durableby lyophilization, for example, and possibly stored away from light. Thedry substance is only dissolved again, i.e., reconstituted, immediatelybefore use. For this purpose two-component systems have become known forre-dissolving the lyophilizate immediately before use.

Other solutions have been sought for carrying out lyophilization of thesolid substance present in the solution using double compartment systemsof this kind, to produce a product that can be re-dissolved subsequentlyor after corresponding storage before use, i.e., to allow the twocomponent systems to be mixed together, while maintaining the sterilityof the two components. The lyophilization of solutions in a syringe isonly possible under special conditions, one problem being that duringthe lyophilization only a very small cross sectional area is availablefor the exchange of gases. The prior art contains numerous proposals forsolving these problems including, for example, those described in U.S.Pat. Nos. 5,788,670; 4,254,768; 8,002,734; and EP Patent PublicationNos. 0 718 002 A2 and 0 295 337 B1; which are all incorporated herein byreference in their entireties. Each of the recited proposals hasinherent disadvantages that make them less useful than the container ofthe present disclosure.

The disadvantages show that there is still a need for an easy to operatedevice for reliably storing and mixing two-component systems and furtherto dispense the mixture (or suspension) of the two components. In anyembodiment, one component (e.g., a second component as described herein)of the two-component system is a gas, a liquid, a gel, a substantiallydry solid (e.g., a lyophilizate), or a paste, and the other component(e.g., a first component as described herein) of the two-componentsystem is a dissolving/dispersing medium (e.g., a gas, a liquid, a gel)therefor. In particular it should be possible to carry outlyophilization directly in the container, while avoiding thedisadvantages of the prior art. Contamination from outside should beruled out as far as possible. In particular, subsequent mixing shouldtake place without removing the components from the sterile inner partof the device and without any external intervention in the systemthereby compromising the sterile condition. The device should also beeasy to store. Furthermore, a method of easily filling a device of thiskind should be provided. The device and the method should be usable onan industrial scale.

The objective described above is achieved by means of the features ofany embodiment of the containers of the present disclosure. Theseembodiments provide a double compartment container for separatelyholding and combining a solid lyophilizate and a liquid reconstitutionmedium therefor.

In the filled state the container also serves to store or preserve thelyophilizate component and a reconstitution medium component therefor inseparate compartments. The two components can be mixed togetherimmediately before use without the need to open the container. Bycombining the two components it is possible for example to prepare aninjectable solution either in dissolved or dispersed form. In anyembodiment, the reconstitution medium may comprise water but also may besome other solvent or mixture of solvents.

The body (e.g., cylindrical body) according to the present disclosure isan essentially elongate hollow body with two open ends which haspreferably been formed integrally, i.e., made in one piece. The“cylindrical” body need not necessarily be cylindrical in shape,although this is the most common shape. Any other geometric shape for anelongate hollow body is possible, such as angular or oval, for example,in which case the closures and separating stopper and the like should bematched to the chosen shape. The material of which the body consists orwhich it contains is not particularly restricted according to theinvention. The container may be selected for example from plastics orglass. In any embodiment, glass may be preferred on account of itstransparency and its compatibility with numerous medical formulations.The body therefore preferably consists of glass or contains glass, asthis produces the least effect on the components contained therein andthe body is preferably transparent. For particular requirements,however, other materials may be suitable, such as special plastics(e.g., cyclic olefin copolymers) or the like. Medical safety isparticularly important, as it is desirable that there be as littleinteraction as possible with the medium contained therein.

The double compartment container further comprises two plugs, a secondplug that is provided at a second end (e.g., in which a solid componentto be mixed is disposed) and a first plug that is provided at a firstend (e.g., in which a liquid component to be mixed with the solidcomponent is disposed) of the container. The plugs are not restrictedfurther provided that the first plug enables pressure to be applied tothe liquid for mixing the two components, so that the second plug movesout of its position and can be pushed into the bypass.

The first plug is preferably a stopper which provides a suitable seal,is inert relative to the medium to be added, and satisfies the sterilityconditions. The first plug should be of such a size or shape that anyopenings proximate the first end of the body are sealed off by it in thesecond position of the stopper.

The second plug arranged in the cylindrical body defines thesize/volume/dimensions of the two compartments and functions as aselective barrier to regulate passage into the second compartment of anycontents (e.g., a liquid) present in the first compartment. The shape ofthe separating stopper is not particularly restricted. It has a suitablethree-dimensional shape to ensure that, in a first position, the twocompartments are sealed off from one another. The separating stopper maybe of any suitable shape: for example, cylindrical shapes, cylindricalshapes with rounded sides, dumbbell-shaped, or cuboid.

In any case, when a force, particularly a manual force, is exerted, thefirst plug should be movable at the first end of the body and hencetowards a component (e.g., a liquid component) disposed in the firstcompartment.

The second plug is preferably an elastic and flexible material and ispreferably made of rubber, such as natural or synthetic rubber,plastics, such as elastomers, thermoplastics, thermoplastic elastomersand the like. The material of the second plug should provide a sealbetween the first and second compartments, e.g., during storage, whenthe second plug is in a first position as described herein.

According to a preferred embodiment according to the present disclosure,the second plug is of a suitable shape, size and/or material that on theone hand will prevent it from being pushed out of its initially fixedand defined position in the cylindrical body but on the other hand willassist the intended displacement of the second plug into the bypass.Conveniently, this can be achieved by the suitable provision of a secondplug having a suitable shape with (adhesive) bumps, lips, beads, ridges,or the like and/or by the choice of a suitable diameter, as described inU.S. Pat. No. 8,002,734.

According to the present disclosure, the term “form” is intended torefer to the outer shape or geometry. The term “size” is intended torefer to the dimensions, i.e., the ratios of magnitude.

In any embodiment, the second plug may have a larger outer diameter thanthe internal diameter of the body, so that sufficient pressure is builtup between the inner wall of the body and the second plug to close theinterface, although the latter is movable within in the body under theeffect of force. The second plug is therefore mounted to be movable ordisplaceable and fluid tight within the body of the container.

In the body there is also a bypass in the form of a bulge that creates adetour line along the body. The bulge may occupy just a portion of thecircumference of the body, or it may extend around the entirecircumference of the body. Generally, the bulge is thinner than thediameter of the second plug. The bypass is not particularly restrictedprovided that its length is shorter than the height of the second plug,so that when the second plug is pushed into the bypass it opens up aplurality of passages for the contents of the first compartment (e.g., afirst component such as a liquid reconstitution medium) to enter thesecond compartment and mix with a second component (e.g., alyophilizate) therein. In other words, the bypass is a region in thebody defines a bypass zone that is shorter along the longitudinal axisthan the length of the second plug along the longitudinal axis, thebypass being arranged and having a size such that, when the second plugis pushed into the bypass zone and is located therein, the firstcomponent disposed in the first compartment is able to flow around thestopper. The bypass provided around at least a portion of the secondplug therefore has a length L along its longitudinal axis which isshorter than the height H of the second plug along its longitudinalaxis. The bypass is therefore preferably shorter than the second plug,thus producing a flow of liquid through the second plug when the secondplug is in the bypass position.

In any embodiment, the bypass may be provided on one or more sides,i.e., on one or more sides of the body of the container. In anyembodiment, the bypass is provided on only one side of the inner wall ofthe body. In a filled state for storage the second plug is located abovethe bypass zone (i.e., proximate the first end) and for mixing it ispushed into the bypass zone. Preferably, therefore, (adhesive) bumps,beads, ridges, or lips are provided in the bypass zone for releasablysecuring the second plug there and ensuring unimpeded passage of thecontents of the first compartment (e.g., a liquid reconstitution medium)into the second compartment (e.g., a solid material or gel that issoluble and/or dispersible in the reconstitution medium).

If the contents of the first compartment are put under pressure when thesecond plug is disposed in a first operational position in the body, thesecond plug initially adheres to the inner wall of the body byfrictional forces. If the frictional adhesion of the second plug to thewall of the body is not sufficient for a particular application, toprevent accidental movement, additional frictional force may be providedby adding projections such as small beads, lips, ridges or bumps to thesecond plug and/or to the inner wall of the body. The pressure thereforedoes not increase in the second compartment. As a result, a differentialpressure is produced between the two compartments. By applyingadditional pressure, the frictional forces are overcome and the secondplug is pushed in the direction of the bypass. As a result of thismovement. At least a portion of the second plug is moved into thebypass, facilitating movement of the first component (e.g., a liquidcomponent) from the first compartment into the second compartment wherethe two components are mixed together.

The present disclosure also provides a method of preparing a containerfor mixing two components, the method comprising the following steps:

-   -   (1) providing a body with a bypass, a first plug, and a second        plug according to any of the embodiments disclosed herein;    -   (2) inserting the second plug into the body to a position        wherein each first opening of the plurality is disposed in the        first portion of the body and is longitudinally aligned with the        bypass;    -   (3) depositing a second component via the second aperture into        the second compartment;    -   (4) optionally, evaporating and evacuating a solvent from the        second compartment, if the second component is dissolved and/or        suspended therein;    -   (5) sealing the second end of the body;    -   (6) depositing a first component into the first compartment via        the first aperture; and    -   (7) inserting the first plug into the body proximate the first        end.

The process will hereinafter be described in detail; any individualfeatures described in relation to the process also apply accordingly tothe double compartment container and vice versa.

The conduits are not particularly restricted as to their shape and size.They may be selected at will depending the volume and/or viscosity offirst component to be moved from the first compartment to the secondcompartment. Possible embodiments of the conduits include round, oval,oblong, triangular or rectangular cross-sectional shapes andcombinations thereof. The conduits may also be arranged at definedspacings and angles from one another.

In any embodiment, the first plug and second plug may be rotationallysymmetrical with respect to the central axis.

The first openings that are provided in the second plug areautomatically closed by pressing in and positioning the second stopperin the container with the first openings contacting the inner surface ofthe wall thereof, so that it is not possible for one of the componentsto pass accidentally through the second plug.

Then the sealed container is taken to a filling station, where in step(6) it is filled with the first component (e.g., a reconstitutingmedium) through the first aperture. After the first compartment has beenfilled with an amount (e.g., a predetermined volume) of the firstcomponent (e.g., a dissolving or dispersing medium for the secondcomponent), the container is fitted with a closure (i.e., the first plugof step (7)). Preferably a stopper may be used as the first plug.However, it is also possible to use any other closure known in the art,provided that it is displaceable under the effect of pressure. It isparticularly advantageous if the first plug at the liquid end is astopper which contains an elastic material or consists thereof, such asplastics, rubber or rubber-like elastic material, such as elastomers,thermoplastics, elastomeric thermoplastics, etc.

The first plug is designed so that it also closes off any opening(s)provided at the first end of the body, so as to seal the containercompletely. It is particularly expedient if the first plug is suppliedand inserted by means of a washing and sterilizing device or anautoclave along sterile corridors. After the container has been sealedit is taken out of the sterile area through an airlock; finally it islabeled and packaged. It will be understood that in this process all thesurfaces and equipment are designed for aseptic operation.

According to the present disclosure the second plug thus performs anumber of different functions. Initially, when assembling and fillingthe container, it functions as a partitioning structure to form twoisolated compartments in the body. Then, the second plug functions as atemporary closure inside the body, to isolate the second component fromthe first component during storage. During use, the second plug performstwo additional functions: 1) when the second plug is urged into thebypass by pressure applied to the first end of the container, theprimary conduits facilitate transfer of the first component from thefirst compartment to the second compartment; and 2) after the firstcomponent has been transferred to the second compartment, the first plugurges the second plug out of the bypass and continued pressure appliedto the first plug at the first end of the container causes the secondplug to expel the blended first and second components in the secondcompartment to be expelled from the container.

In any embodiment, the double compartment container of the presentdisclosure is a container configured for single or multiple uses.

The measurements of the double compartment container depend on thevolume of the mixture or dispersion which is to be produced. Forexample, in human medical practice, volumes of 10 ml are rarelyexceeded, which means that volumes of up to about 20 ml are usuallysufficient. In exceptional cases and for veterinary use however it ispossible to exceed these volumes.

The present disclosure also provides a method of mixing a firstcomponent (e.g., a solid lyophilizate) and a second component (e.g., aliquid reconstitution medium) in a double compartment container, thecontainer comprising:

-   -   a body having a longitudinal axis, a first end with a first        aperture, a second end including a second aperture opposite the        first end, and a bypass disposed between the first and second        ends;        -   wherein the bypass has a length L;    -   a first plug slidably disposed in the body proximate the first        end;    -   a second plug slidably disposed in the body between the first        plug and the second end;        -   wherein the first and second plugs define opposite ends of a            first compartment disposed in the body between them;        -   wherein a second compartment is disposed in the body between            the second plug and the second end;        -   wherein the second plug includes:            -   a top surface facing the first plug;            -   a bottom surface facing the second end;            -   a side wall extending between the top surface and the                bottom surface, the side wall comprising a                circumferential first seal having a first edge proximate                the top surface and a circumferential second seal having                a second edge proximate the bottom surface; and            -   a plurality of spaced-apart primary conduits extending                through the second plug, each primary conduit extending                from separate first openings in the side wall to a                second opening in the bottom surface;            -   wherein the first openings are disposed between the                circumferential first seal and the circumferential                second seal            -   wherein at least one of the primary conduits directs                liquid flow out of the second opening along a line that                is not parallel to the longitudinal axis;            -   wherein a distance D extends longitudinally from the                first edge to the second edge;            -   wherein a distance E extends longitudinally from the                first edge to the first opening that is nearest the                first edge;        -   wherein D≧L and E<L.

In order to mix the two components, the first plug is pushed towards thesecond plug by the application of external force, particularly forceexerted manually, and at the same time pressure is applied to the firstplug, causing the second plug to be pushed into the bypass, so that thefirst component has a passage to the compartment containing the secondcomponent. The two components may thus be mixed together withoutaffecting the sterile conditions of the double compartment container.

Preferably the first plug is a stopper, particularly a rubber stopper.The two components are particularly preferably mixed together by holdingthe container vertically, i.e., with the second end oriented below thefirst end. In any embodiment, while the two components are mixed, thesecond end is fluidically sealed e.g., using a sealing disc with aflanged cap, but it is also possible to use any other suitable,optionally removable, closure.

The pressure on the first plug may be applied using the fingers, a stemor plunger attached to or in contact with the first plug, a suitablepunch, or other suitable mechanical actuator, impulse, or means. Boththe first component and the second plug then move toward the second end.The second plug moves into the bypass position and thereby opens afluidic pathway between the first compartment and the second compartmentvia the plurality of primary conduits. The pressure exerted on the firstcomponent by the first plug allows the first component to flow throughthe fluidic pathway opened up by the bypass between the first and secondcompartments and to enter the second compartment containing the secondcomponent (e.g., a lyophilizate).

The first component (e.g., a reconstitution medium) combines with thesecond component (e.g., a solid lyophilizate) and the latter isdissolved and or suspended in the former. The first plug at the firstend can be pressed right through to the second plug. The solution orsuspension is finally completely reconstituted and is ready for use.

In any embodiment, combined (e.g., reconstituted) mixture of the firstand second components can be distributed out of the container throughthe second aperture described herein. In these embodiments, thefluid-tight seal, if present on the container is converted from a closedstate to an open state (e.g., by removing a cap, opening a valve, and/orpiercing a pierceable seal).

The present disclosure also relates to the use of the containeraccording to the invention in human and veterinary medicine.

The container and methods of the present disclosure have a number ofadvantages:

According to the present disclosure, in one embodiment, a doublecompartment container with a lyophilizate and a reconstitution solutionis provided. Using the container according to the disclosure it ispossible to dry a substance which is unstable in solution directly inthe lyophilizer and then provide a double compartment system in thesingle body. Thus the construction according to the present disclosureallows problem-free storage of the two-component system withoutpremature mixing and hence a loss of efficacy of the components takingplace. The two-component system provided according to the presentdisclosure may be stored in the sterilized, pre-filled state ready foruse. The mixing of the two components takes place after storageimmediately before use. The double compartment container can be thrownaway after use.

Using the double compartment container according to the invention adesired solution or suspension may be prepared immediately before use,resulting not only in a fast and reliable system, but also ease ofmanufacture and filling. This is an all-in-one solution, i.e., acontainer is obtained having two compartments which are separated fromone another by a plug.

Using the double compartment container according to the invention it ispossible to carry out reconstitution of a lyophilizate in a sealedtwo-compartment system, by simple maneuvers, without having to open itand, thereby, possibly expose it to undesirable external microbial,chemical or physical influences.

The double compartment system described allows the container already inthe lyophilizer to be tightly sealed. This gives rise to the advantagesthat contamination of the lyophilizate, particularly by particles,pathogens, and any foreign bodies, are avoided. Moreover, thelyophilizate is protected from moisture and oxygen. The container can beused as primary pack aging and stored in its clearly labeled form. Theuse of two component systems, particularly lyophilized preparations, canthus be made simpler. The container is not limited in any way and may beused for example in so called pen systems which are already on themarket.

Turning to the drawings, FIG. 1 is a schematic side view, partially insection, of one embodiment of a body 100 of a container according to thepresent disclosure. The body 100 has a first end 102 and a second end104 opposite the first end. The first end 102 has a first aperture 103that provides access to (or egress from) the interior of the body 100.The second end 104 has a second aperture 107 that also provides accessto (or egress from) the interior of the body 100. Optionally, the secondaperture 107 may be smaller than the first aperture 103, as shown inFIG. 1.

In any embodiment, the second end further comprises a coupling structure106. The coupling structure 106 can be used to couple (e.g., fluidicallycouple) the body 100 to an infusion device. Non-limiting examples ofsuitable coupling structures include Luer fittings (e.g., Luer-slip andLuer-lock type fittings) that are well known in the art. Nonlimitingexamples of infusion devices include a catheter, a cannula, a needle, ora microneedle device.

In any embodiment, the coupling structure may comprise a valve (notshown). The valve may have an open position that permits fluid flow intoor out of the container and a closed position that does not permit flowinto our out of the container.

The body 100 of the container further comprises a bypass 110. The bypass110 divides the body 100 into three portions: a first portion 100 aproximate the first end 102, a second portion 100 b proximate the secondend 104, and a bypass portion 100 c disposed between the first portionand the second portion of the body. The cross-sectional diameter of theinterior of the body 100 is larger in the bypass portion 100 c than inthe first portion 100 a and second portion 100 b.

FIG. 2 shows a top view of the body 100 of FIG. 1. The body 100comprises wall 101 that defines a cylindrical inner volume that isbounded by a first aperture 103 at one end and a smaller second aperture107 at the other end. Also shown in FIG. 2 is the bypass 110 in whichthe cross-sectional area of the interior volume of the body 100 islarger than in other portions of the body.

The body 100 can be fabricated from any suitable material for containingtwo components that are intended to be mixed together. Preferably, thematerial is substantially inert with respect to interaction with eitherof the components to be mixed. In any embodiment, the body 100 is moldedglass or plastic (e.g., thermoplastic) material, both of which canprovide visual observation of the mixing process as it proceeds in thecontainer. Alternatively, the body 100 may be fabricated from a metal(e.g., stainless steel) using processes that are well known in the art.

FIG. 3 shows a schematic side view, partially in section, of oneembodiment of a container 1000 according to the present disclosure. Thecontainer 1000 comprises a body 100 having a first end 102 with a firstaperture 103, a second end 104, and a bypass 110 as described herein;the body 100 having a first plug 200 and a second plug 300 disposedtherein. At least a portion of the circumferential first seal (describedbelow) of the second plug 300 is disposed in the first portion (firstportion 100 a of FIG. 1) of the body 100. In this position, the secondplug 300 divides the interior volume of the body 100 into twofluidically-isolated portions—a first compartment 120 proximate thefirst end 102 of the body and a second compartment 130 proximate thesecond end 104 of the body. Although not a requirement of everyembodiment of the container of the present disclosure, in theillustrated embodiment of FIG. 3, the first compartment contains aliquid first component 125 and the second compartment contains a solidsecond component 135.

The container 1000 further comprises an optional openable seal 400 thatfluidically seals the second end 104 of the body 100. In any embodiment,the seal 400 may be a fluid-tight seal wherein, in a closedconfiguration, the fluid-tight seal prevents fluid flow into or out ofthe second aperture. In any embodiment, the openable seal 400 maycomprise a durable seal such as a plastic cap, for example, attached byfriction fit to the second end 104 of the body 100. Alternatively oradditionally, the openable seal 400 may comprise a frangible seal suchas a plastic or metal foil film, for example, that is adhesively securedto the second end 104 of the body 100.

At least partially disposed in the body 100 proximate the first end 102is a first plug 200. The first plug 200 may take the form of any shapethat can form a moveable, fluid-tight seal in the body 100 of thecontainer 1000. Optionally, the first plug 200 may comprise one or moreextension 202 extending from a central body 204. The extensions 202 canreduce the amount of friction between the first plug 200 and the body100, thereby facilitating movement (i.e., reducing the amount of forcenecessary for movement) of the first plug 200 through the body. In theillustrated embodiment of FIG. 3, the extensions 202 provide seals thathold the liquid first component 125 in the first compartment 120 duringa storage period until the first and second components are mixed in thecontainer 1000 as described herein.

The first plug 200 is preferably an elastic and flexible material and ispreferably made of rubber, such as natural or synthetic rubber,plastics, such as elastomers, thermoplastics, thermoplastic elastomersand the like using processes (e.g., injection molding processes) thatare well known in the art.

FIGS. 4A-4C show various views of one embodiment of the second plug 300of FIG. 3. The second plug 300 is shaped and dimensioned to sealinglyfit inside the body of a container of the present disclosure. The secondplug 300 has an axial top surface 340 that faces the first end of thebody, an axial bottom surface 342 that faces the second end of the body,and a plurality of primary conduits (primary conduits 352 a and 352 b,respectively) extending therethrough. Each of the primary conduitsextends from a radial first opening (first openings 350 a and 350 b,respectively) to a second opening (second openings 354 a and 354 b,respectively) at the bottom surface 342 of the second plug 300. Thesecond plug may have 2, 3, 4, 5, 6, 8, 10, 12, 15, or 20 primaryconduits extending therethrough. Thus, in any embodiment, the secondplug may include 2-4 primary conduits, 2-6 primary conduits, 2-8 primaryconduits, 2-10 primary conduits, 2-12 primary conduits, 4-10 primaryconduits, or 10-20 primary conduits.

At least one of the primary conduits directs liquid flow out of thesecond opening along a line that is not parallel to the longitudinalaxis “X” of the second plug 300, as shown by lines “M” and “N” in FIG.4A. In any embodiment, at least one of the primary conduits (e.g.,primary conduit 352 b) directs liquid flow out of the second opening(e.g., second opening 354 b) along a line that forms a compound anglewith respect to the longitudinal axis X of the second plug 300, as shownin FIGS. 4A-4C. In any embodiment, two or more of the primary conduitseach directs liquid flow out of its second opening along a line thatforms a compound angle with respect to the longitudinal axis. Theconfiguration of the primary conduits wherein at least one directsliquid flow alone a line that is not parallel to the longitudinal axiscreates additional turbulence (e.g., by deflection of the liquid flowoff the side wall of the body) such that the component disposed in thesecond compartment can be mixed more rapidly and thoroughly that whenthe liquid flow is directed along a line that is parallel to thelongitudinal axis.

In any embodiment (not shown), at least one of the plurality of primaryconduits directs liquid flow out of the second opening along a line thatis not parallel to the longitudinal axis and at least one of theplurality of primary conduits directs liquid flow out of the secondopening along a line that is substantially parallel to the longitudinalaxis. “Substantially parallel”, as used herein refers to a line thatintersects the longitudinal axis to form an angle that is less 3°

The second plug 300 is preferably an elastic and flexible material andis preferably made of rubber, such as natural or synthetic rubber,plastics, such as elastomers, thermoplastics, thermoplastic elastomersand the like using processes (e.g., compression molding processes) thatare well known in the art. The primary conduits may be formed while thesecond plug is formed or, alternatively, may be formed (e.g., using alaser drilling process) after the second plug is formed.

The second plug 300 (see FIG. 5) comprises at least two circumferentialseals (circumferential seals 344 and 346, respectively) that, whendisposed in the first or second portion of the body of the container ofthe present disclosure, form a fluid-tight seal in the container. Thecircumferential first seal 344 comprises a first edge 345 proximate thetop surface 340 of the second plug 300. The circumferential second seal346 comprises a second edge 347 proximate the bottom surface 342 of thesecond plug 300. The first openings (first openings 350 a and 350 b,respectively) are disposed between the circumferential first seal 344and the circumferential second seal 346. A distance “E” extends from thefirst edge 345 to the first opening (i.e., first opening 350 a of FIG.5) that lies closest to the first edge. Distance E is less than distanceL. A distance “D” extends longitudinally from the first edge 345 to thesecond edge 347.

FIG. 6 shows side views of the body 100 and second plug 300 of thecontainer 1000 of FIG. 3. In the illustrated embodiment, the axiallength D between the first edge 345 and second edge 347 of the secondplug 300 is greater than the axial length L of the bypass 110 of thebody 100. This relationship ensures that, as the second plug 300 movesthrough the bypass region (see bypass region 100 c of FIG. 1), eitherthe first edge 345 and/or the second edge 347 is in circumferentialcontact with the body 100. This further ensures that any fluid flow fromthe first end 102 side of the second plug 300 to the second end 104 sideof the second plug must be through one or more of the plurality ofprimary conduits (i.e., primary conduits 350 a and 350 b, respectively).

In use, a container according to the present disclosure can be used tomix two components (e.g., a fluid component (e.g., a liquid) and a solidcomponent) that have been kept isolated from each other in the containerfor a period of time. FIGS. 7-9 show schematic side views, partially insection of a container 1000 in various stages of a process of mixing twocomponents according to the method.

FIG. 7 shows a container 1000 comprising a body 100 with a first end102, a second end 104, and a bypass 110, each as described herein.Disposed in the first portion (first portion 100 a of FIG. 1) of thebody 100 proximate the first end 102 is a first plug 200, as describedherein. Located in a first operational position in the first portion(first portion 100 a of FIG. 1) of the body 100 is a second plug 300 asdescribed herein. The second plug 300 comprises a plurality of primaryconduits (primary conduits 352 a and 352 b) extending therethrough asdisclosed herein. Positioned between the first plug 200 and the secondplug 300 is a first compartment 120 containing a first component 125(e.g., a liquid in which a second component can be dissolved and/orsuspended). In any embodiment, the first component 125 can be an aqueousliquid selected form the group consisting of water, buffered water, anaqueous saline solution, and combinations thereof.

In any embodiment, the first component 125 may be present in the firstcompartment in a predetermined quantity. Positioned between the secondplug 300 and the second end 104 is a second compartment 130 containing asecond component 135 (e.g., a lyophilized solid capable of dissolving orsuspending in the first component 125). In any embodiment, the secondcomponent 135 may be present in the form of a powder. In any embodiment,the second component may comprise a predetermined quantity of apharmaceutically-active compound. In any embodiment the powder maycomprise a vaccine. In any embodiment the powder may comprise a smallmolecule, a protein, a peptide a glycoprotein, a hormone, or apolynucleotide. The powder may be a naturally derived compound or asynthetic compound. The second end 104 of the container 1000 furthercomprises a seal 400 that is impervious to the first and secondcomponents (125 and 135, respectively) disposed in the container. Thus,the container 1000 shown in FIG. 7 has a first component 125 and secondcomponent 135 contained therein in a configuration that can be used tostore the components prior to the mixing process described herein.

According to the method, the first plug 200 is urged under pressure(e.g., manual or machine pressure) into the body 100 toward the secondend 104, as shown in FIG. 8. In order to facilitate movement of thefirst plug 200 into the body, a pushing object (e.g., a stem, not shown,optionally attached to the first plug) can be used to apply force to thefirst plug in the direction of arrow “A”. Force against the first plug200 is translated through the first compartment 120 and first component125 to the second plug 300, causing the second plug to move toward thesecond end 104 and into a second operational position, as shown in FIG.8. As the top surface 340 (shown in FIG. 7) of the second plug 300 movesinto the bypass 110, the force against the first plug 200 caused thefirst component 125 to move into the bypass 110 (as shown by arrow “B”,through the primary conduits 352 a and 352 b, and out the second plug300 into the second compartment 130, as shown by arrows “C” in FIG. 8.Upon entering the second compartment 130, flow of the first component125 causes turbulence (not shown), which facilitates rapid dissolutionand/or suspension of the second component 135 causing formation of themixture 170 as substantially all of the first component 125 istransferred under pressure from the first compartment 120 to the secondcompartment 130. Advantageously, in any embodiment, the method does notrequire addition shaking (e.g., manual and/or mechanically-assistedshaking) in order to achieve a uniform mixture (or suspension) of thefirst and second components after the first component has beentransferred into the second compartment.

In use, a container according to the present disclosure can be used in amethod to mix two components (e.g., a fluid component (e.g., a liquid)and a solid component) and further to distribute the combination of thetwo components. FIGS. 7-10 show schematic side views, partially insection of a container 1000 in various stages of a process of mixing twocomponents according to the method.

It is contemplated that management of air pressure withinmulti-compartmental containers is a factor during storage and/orsubsequent use of the container to mix the components disposed in thecompartments. Avoiding the build-up of air pressure within the secondcompartment will prevent excessive back pressure from developing as thefirst and second plugs are urged toward the second end of the container.Possible solutions include, but are not limited to, evacuating air fromthe second compartment (e.g., during lyophilization of the secondcomponent) or inserting a vent (e.g., a needle) through the secondaperture or actuating a valve or vent (not shown) at the second aperturewhile the first component is transferred form the first compartment tothe second compartment.

This method includes the steps shown in FIGS. 7-9 and described above.After the first and second components have been combined to form themixture 170, the seal 400 is removed from the second end of thecontainer, thereby exposing the second aperture (not shown). Continuedforce against the first plug 200 in the direction of arrow A istranslated to the second plug and the mixture 170, causing the mixture170 to flow out the second end 104, as shown by arrow “P” in FIG. 10.

In any embodiment of the container of the present disclosure, the bottomsurface of the second plug may take a form other than a plane that isorthogonal to the longitudinal axis of the second plug. Thus, in anyembodiment, the bottom surface of the second plug may take the form of anon-planar shape. Non-limiting examples of suitable shapes of the bottomsurface include a segment of a sphere, a hemisphere, a catenoid, aparaboloid of revolution, a truncated cylinder, a cone, a truncatedcone, and a frustum. Advantageously, the shaped surface can perform atleast two functions: 1) a projecting bottom surface of the second plugmay better conform to the shape of the second aperture at the second endand, thus, facilitate expulsion of the entire mixture from thecontainer, and 2) a shaped bottom surface of the second plug can createadditional turbulence in the second compartment, thereby facilitatingmore-rapid dissolution and/or dispersion of the second component intothe first component.

FIGS. 11-13 show three embodiments of second plugs (301, 302, and 303,respectively) having shaped bottom surfaces (342 a, 343 b, and 342 c,respectively), each second plug having a plurality of primary conduits352 extending therethrough. In each of the illustrated embodiments, atleast one of the primary conduits 352 directs liquid flow out of thesecond opening along a line that is not parallel to the longitudinalaxis (not shown). The second plug 301 of FIG. 11 comprises aconical-shaped bottom surface 342 a. The second plug 302 of FIG. 12comprises a frustoconical-shaped bottom surface 342 b. The second plug303 of FIG. 13 comprises a hemispherical-shaped bottom surface 342 c.

Exemplary Embodiments

Embodiment A is a container, comprising:

-   -   a body having a longitudinal axis, a first end with a first        aperture, a second end including a second aperture opposite the        first end, and a bypass disposed between the first and second        ends;        -   wherein the bypass has a length L;    -   a first plug slidably disposed in the body proximate the first        end;    -   a second plug slidably disposed in the body between the first        plug and the second end;        -   wherein the first and second plugs define opposite ends of a            first compartment disposed in the body between them;        -   wherein a second compartment is disposed in the body between            the second plug and the second end;        -   wherein the second plug includes:            -   a top surface facing the first plug;            -   a bottom surface facing the second end;            -   a side wall extending between the top surface and the                bottom surface, the side wall comprising a                circumferential first seal having a first edge proximate                the top surface and a circumferential second seal having                a second edge proximate the bottom surface; and            -   a plurality of spaced-apart primary conduits extending                through the second plug, each primary conduit extending                from separate first openings in the side wall to a                second opening in the bottom surface;            -   wherein the first opening is disposed between the                circumferential first seal and the circumferential                second seal;            -   wherein at least one of the primary conduits directs                liquid flow out of the second opening along a line that                is not parallel to the longitudinal axis;            -   wherein a distance D extends longitudinally from the                first edge to the second edge;            -   wherein a distance E extends longitudinally from the                first edge to the first opening that is nearest the                first edge;        -   wherein D≧L and E<L.

Embodiment B is the container of Embodiment A, wherein at least one ofthe primary conduits directs liquid flow out of its second opening alonga line that forms a compound angle with respect to the longitudinalaxis.

Embodiment C is the container of Embodiment B, wherein two or more ofthe primary conduits each directs liquid flow out of its second openingalong a line that forms a compound angle with respect to thelongitudinal axis.

Embodiment D is the container of any one of the preceding Embodiments,wherein the bottom surface substantially defines a shape selected fromthe group consisting of a segment of a sphere, a hemisphere, a catenoid,a paraboloid of revolution, a truncated cylinder, a cone, a truncatedcone, and a frustum.

Embodiment E is the container of any one of the preceding Embodiments;wherein the second compartment comprises a lyophilized reagent.

Embodiment F is the container of Embodiment E, wherein the lyophilizedreagent comprises a predetermined amount of a pharmaceutically-activecompound.

Embodiment G is the container of any one of the preceding Embodiments,further comprising a stem operatively coupled to the first plug.

Embodiment H is the container of any one of the preceding Embodiments,wherein the second aperture comprises a coupling structure.

Embodiment I is the container of any one of the preceding Embodiments,wherein the container includes an openable fluid-tight seal proximatethe second aperture wherein, in a closed configuration, the fluid-tightseal prevents fluid flow into or out of the second aperture.

Embodiment J is the container of Embodiment H or Embodiment I, whereinthe coupling structure is adapted to couple a needle or a microneedledevice to the container.

Embodiment K is the container of Embodiment J, wherein the couplingstructure comprises a valve having an open position that permits fluidflow out of the container and a closed position that does not permitfluid flow out of the container.

Embodiment L is the container of any one of the preceding Embodiments;wherein the first compartment contains a predetermined quantity of afirst component to be mixed with a second component; wherein, at ambienttemperature, the first component comprises a gas, a liquid, or a gel.

Embodiment M is the container of Embodiment L, wherein the secondcompartment contains a predetermined quantity of a second component tobe mixed with the first component; wherein, at ambient temperature, thesecond component comprises a gas, a liquid, a gel, a substantially drysolid, or a paste.

Embodiment N is a method of mixing first and second components of acomposition, the method comprising:

bringing the first component, which is disposed in the first compartmentof a container of Embodiment M, into contact with the second component,which is disposed in the second compartment of the container;

-   -   wherein the first component comprises a fluid;    -   wherein the second component comprises a fluid or a solid;    -   wherein bringing the first component into contact with the        second component comprises urging the first plug toward the        second end until at least one first opening is in fluid        communication with the bypass, the first compartment, and the        second compartment;    -   wherein urging the first plug toward the second end comprises        urging at least a portion of the first component from the first        compartment into the second compartment.

Embodiment O is a method of mixing first and second components of acomposition and distributing the composition, the method comprising:

bringing the first component, which is disposed in the first compartmentof a container of Embodiment M, into contact with a second component,which is disposed in the second compartment of the container;

-   -   wherein the first component comprises a fluid;    -   wherein the second component comprises a fluid or a solid;    -   wherein bringing the first component into contact with the        second component comprises urging the first plug toward the        second end until at least one first opening is in fluid        communication with the bypass, the first compartment, and the        second compartment;    -   wherein urging the first plug toward the second end comprises        transferring a predetermined volume of the first component from        the first compartment into the second compartment to form the        composition; and    -   converting the second end of the container from a closed state        to an open state;    -   wherein, after the predetermined volume of the first component        is transferred into the second compartment, urging the first        plug toward the second end further comprises urging the second        plug toward the second end;    -   wherein urging the second plug toward the second end comprises        distributing at least a portion of the composition out of the        body via the second aperture.

Embodiment P is the method of Embodiment O, wherein converting thesecond end of the container from a closed state to an open statecomprises converting a fluid-tight seal from a closed state to an openstate.

Embodiment Q is the method of Embodiment O or Embodiment P, whereinconverting the container from a closed state to an open state comprisesadjusting a valve from a closed state to an open state.

Embodiment R is the method of any one of Embodiments O through Q,further comprising coupling the second end to an infusion device.

Embodiment S is the method of Embodiment R, wherein the infusion deviceis selected from a group consisting of a catheter, a cannula, a needle,or a microneedle device.

Embodiment T is the method of any one of Embodiment O through S, whereinthe first component comprises a liquid, wherein the second componentcomprises a substantially dry solid.

Embodiment U is the method of Embodiment T, wherein the substantiallydry solid comprises a powder.

Embodiment V is the container of any one of Embodiments A through M,wherein at least one of the plurality of primary conduits directs liquidflow out of the second opening along a line that is not parallel to thelongitudinal axis and at least one of the plurality of primary conduitsdirects liquid flow out of the second opening along a line that issubstantially parallel to the longitudinal axis.

The complete disclosure of all patents, patent applications, andpublications, and electronically available material cited herein areincorporated by reference. In the event that any inconsistency existsbetween the disclosure of the present application and the disclosure(s)of any document incorporated herein by reference, the disclosure of thepresent application shall govern. The foregoing detailed description andexamples have been given for clarity of understanding only. Nounnecessary limitations are to be understood therefrom. The invention isnot limited to the exact details shown and described, for variationsobvious to one skilled in the art will be included within the inventiondefined by the claims.

All headings are for the convenience of the reader and should not beused to limit the meaning of the text that follows the heading, unlessso specified.

The invention illustratively described herein suitably may be practicedin the absence of any element(s) not specifically disclosed herein.Thus, for example, in each instance herein any of the terms“comprising”, “consisting essentially of”, and “consisting of” may bereplaced with either of the other two terms. The terms and expressionswhich have been employed are used as terms of description and not oflimitation, and there is no intention that in the use of such terms andexpressions of excluding any equivalents of the features shown anddescribed or portions thereof, but it is recognized that variousmodifications are possible within the scope of the invention claimed.Thus, it should be understood that although the present invention hasbeen specifically disclosed by preferred embodiments and optionalfeatures, modification and variation of the concepts herein disclosedmay be resorted to by those skilled in the art, and that suchmodifications and variations are considered to be within the scope ofthis invention as defined by the appended claims.

1. A container, comprising: a body having a longitudinal axis, a firstend with a first aperture, a second end including a second apertureopposite the first end, and a bypass disposed between the first andsecond ends; wherein the bypass has a length L; a first plug slidablydisposed in the body proximate the first end; a second plug slidablydisposed in the body between the first plug and the second end; whereinthe first and second plugs define opposite ends of a first compartmentdisposed in the body between them; wherein a second compartment isdisposed in the body between the second plug and the second end; whereinthe second plug includes: a top surface facing the first plug; a bottomsurface facing the second end; a side wall extending between the topsurface and the bottom surface, the side wall comprising acircumferential first seal having a first edge proximate the top surfaceand a circumferential second seal having a second edge proximate thebottom surface; and a plurality of spaced-apart primary conduitsextending through the second plug, each primary conduit extending fromseparate first openings in the side wall to a second opening in thebottom surface; wherein the first opening is disposed between thecircumferential first seal and the circumferential second seal whereinat least one of the primary conduits directs liquid flow out of thesecond opening along a line that is not parallel to the longitudinalaxis; wherein a distance D extends longitudinally from the first edge tothe second edge; wherein a distance E extends longitudinally from thefirst edge to the first opening that is nearest the first edge; whereinD≧L and E<L.
 2. The container of claim 1, wherein at least one of theprimary conduits directs liquid flow out of its second opening along aline that forms a compound angle with respect to the longitudinal axis.3. The container of claim 2, wherein two or more of the primary conduitseach directs liquid flow out of its second opening along a line thatforms a compound angle with respect to the longitudinal axis.
 4. Thecontainer of claim 1, wherein the second compartment comprises alyophilized reagent.
 5. The container of claim 4, wherein thelyophilized reagent comprises a predetermined amount of apharmaceutically-active compound.
 6. The container of claim 1, furthercomprising a stem operatively coupled to the first plug.
 7. Thecontainer of claim 1, wherein the second end comprises a couplingstructure.
 8. The container of claim 1, wherein the container includesan openable fluid-tight seal proximate the second aperture wherein, in aclosed configuration, the fluid-tight seal prevents fluid flow into orout of the second aperture.
 9. The container of claim 7, wherein thecoupling structure is adapted to couple a needle or a microneedle deviceto the container.
 10. The container of claim 9, wherein the couplingstructure comprises a valve having an open position that permits fluidflow out of the container and a closed position that does not permitfluid flow out of the container.
 11. The container of claim 1; whereinthe first compartment contains a predetermined quantity of a firstcomponent to be mixed with a second component; wherein, at ambienttemperature, the first component comprises a gas, a liquid, or a gel.12. The container of claim 11; wherein the second compartment contains apredetermined quantity of a second component to be mixed with the firstcomponent; wherein, at ambient temperature, the second componentcomprises a gas, a liquid, a gel, a substantially dry solid, or a paste.13. A method of mixing first and second components of a composition, themethod comprising: bringing the first component, which is disposed inthe first compartment of a container of claim 12, into contact with thesecond component, which is disposed in the second compartment of thecontainer; wherein the first component comprises a fluid; wherein thesecond component comprises a fluid or a solid; wherein bringing thefirst component into contact with the second component comprises urgingthe first plug toward the second end until at least one first opening isin fluid communication with the bypass, the first compartment, and thesecond compartment; wherein urging the first plug toward the second endcomprises urging at least a portion of the first component from thefirst compartment into the second compartment.
 14. A method of mixingfirst and second components of a composition and distributing thecomposition, the method comprising: bringing the first component, whichis disposed in the first compartment of a container of claim 12, intocontact with the second component, which is disposed in the secondcompartment of the container; wherein the first component comprises afluid; wherein the second component comprises a fluid or a solid;wherein bringing the first component into contact with the secondcomponent comprises urging the first plug toward the second end until atleast one first opening is in fluid communication with the bypass, thefirst compartment, and the second compartment; wherein urging the firstplug toward the second end comprises transferring a predetermined volumeof the first component from the first compartment into the secondcompartment to form the composition; and converting the second end ofthe container from a closed state to an open state; wherein, after thepredetermined volume of the first component is transferred into thesecond compartment, urging the first plug toward the second end furthercomprises urging the second plug toward the second end; wherein urgingthe second plug toward the second end comprises distributing at least aportion of the composition out of the body via the second aperture. 15.The method of claim 14, wherein converting the second end of thecontainer from a closed state to an open state comprises converting afluid-tight seal from a closed state to an open state.
 16. The method ofclaim 14, wherein converting the container from a closed state to anopen state comprises adjusting a valve from a closed state to an openstate.
 17. The method of claim 14, further comprising coupling thesecond end to an infusion device.
 18. The method of claim 17, whereinthe infusion device is selected from a group consisting of a catheter, acannula, a needle, or a microneedle device.
 19. The method of claim 14,wherein the first component comprises a liquid, wherein the secondcomponent comprises a substantially dry solid.
 20. The method of claim19, wherein the substantially dry solid comprises a powder.